This invention relates to pyrrolidinone and pyrrolidin-thione pharmaceuticals, and more particularly, to 1-methyl-4-phenylpyrrolidin-2-ones, pharmaceutical compositions containing them, and their use in modulating 17xcex2-Hydroxysteroid Dehydrogenase type II (17xcex2-HSD II) enzyme mediated processes.
Microsomal 17xcex2-Hydroxysteroid Dehydrogenase of human endometrium and placenta (designated 17xcex2-HSD type II) was cloned by expression cloning, and found to be equally active using androgens and estrogens as substrates for oxidation (Andersson S., Molecular genetics of androgenic 17xcex2-Hydroxysteroid Dehydrogenases. J. Steroid Biochem. Molec. Biol., 55, 533-534 (1995)). The recombinant 17xcex2-HSD type II converts the highly active 17xcex2-hydroxysteroids such as estradiol (E2), testosterone (T), and dehydrotestosterone (DHT) to their inactive keto forms. In addition, the type II enzyme can, to a lesser extent, also convert 20xcex2-hydroxyprogesterone (20xcex2P) to progesterone (P) (Wu L, Einstein M, Geissler W M, Chan H K, Elliston K O, and Andersson S., Expression cloning and characterization of human 17xcex2-hydroxysteroid dehydrogenase type 2, a microsomal enzyme possessing 20a-hydroxysteroid dehydrogenase activity. J. Biol. Chem., 268(12), 964-969 (1993)). The broad tissue distribution together with the predominant oxidative activity of 17xcex2-HSD II suggest that the enzyme may play an essential role in the inactivation of highly active 17xcex2-hydroxysteroids, resulting in diminished sex hormone action in target tissues. Dong and colleagues (Dong Y, Qiu Q Q, Debear J, Lathrop W F, Bertolini D, Tamburini P P, 17p-hydroxysteroid dehydrogenases in human bone cells. J. Bone Min. Res., 13, 1539-1546 (1998)) showed significant 17xcex2-HSD II activity in cultured human osteoblasts and osteoblast-like osteosarcoma cells MG63 and TE85, but not in SaOS-2. The potential for interconversion of E1 to E2, T to A, and DHT to A by bone cells could therefore represent important mechanism for the local regulation of intracellular ligand supply for the estrogen and androgen receptors in the osteoblasts and other steroid sensitive cells. This modulation of steroid levels may be employed for a wide variety of indications, including those shown in the lettered paragraphs below.
A1) for the prevention and treatment of osteoporosis (Turner et al., Endocr. Rev., 16, 275 (1994); Lindsay et al., Lancet, 1, 1038 (1976); Stevenson et al., Lancet, 336, 265 (1990); Lindsay et al., Obstet. Gynecol., 76, 290 (1990); Lindsay and Cosman: The Pharmacology of Estrogensin Osteoporosis. In: Principles of Bone Biology, Ed.: J P Bilezikian, L G Raisz, G A Rodan, Academic Press, 1063 (1996); Schmidt et al.: Anabolic Steroid Effects on Bone in Women. In: Principles of Bone Biology, Ed.: J P Bilezikian, L G Raisz, G A Rodan, Academic Press, 1125 (1996).
B1) for the treatment of ovarian cancer (Moghrabi et al., TEM, 9, 265 (1998); Sato et al., Cancer Res., 51, 5118 (1991));
B2) for the treatment of breast cancer (Risinger et al., Nature Genet., 7, 98 (1994); Tremblay, et al., J. Steroid Biochem. Mol. Biol., 66, 179 (1998); Speirs et al., Brit. J. Cancer, 81, 690 (1999));
B3) for the treatment of endometrial cancer (Miettinen et al., Biochem. J., 314, 839 (1996));
B4) for the treatment of endometriosis (Vihko et al., Med. Manage. Endometriosis, [Symp.] 79 (1984); Vihko et al., Ann. N.Y. Acad. Sci., 622, 392 (1991));
C1) for the treatment of prostate cancer (Elo et al., J. Cancer, 66, 37 (1996));
D1) for the treatment of acne (Odlind et al., Clin. Endocrinol., 16, 243 (1982));
D2) for the treatment of psoriasis (Henseler et al., J. Am. Acad. Dermatol., 13, 450 (1985));
D3) for the treatment of androgen-dependent hair-loss (Hughes et al., Endocrinology, 138, 3711 (1997));
E1) non-insulin-dependent diabetes mellitus (Corbould et al., J. Clin. Endocrinol. Metab., 83, 187 (1998));
F1) for cholesterol lowering (Karjalainen, A. et al., Arterioscler.Thromb.Vasc.Biol., 20 1101 (2000)).